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PURPOSE Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months ( P = .0570). The objective response rate was 4.6% v 2.7% ( P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

3566 Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.

TPS6093 Background: Since patients with early-stage oral cavity cancer (OCC; T1-2N0M0; AJCC 8th ed) have a 20-30% rate of occult nodal metastases despite clinical and radiographic assessment, standard of care treatment includes elective neck dissection (END). Many patients have comprehensive surgical management of the regional cervical nodal basin even though the majority of those necks (70-80%) will not contain disease. Assessment of draining first echelon lymph nodes by sentinel lymph node (SLN) biopsy (Bx), a less invasive surgical procedure, may provide an alternative to END, while potentially reducing morbidity and cost. A decisive clinical trial comparing SLN Bx versus END can focus the HNC clinical and research community and resources on establishing the standard of care for management of the neck in early-stage OCC. Methods: In order to address the efficacy of SLN Bx in this population, we recently activated an international multi-institutional phase II/III prospective trial randomizing patients to two surgical arms: SLN Bx and END. PET/CT is an integral imaging biomarker in this trial. A node-negative PET/CT study with central read is required before randomization. Patients with a positive PET/CT central result will remain in a registry to compare imaging findings with final neck pathology. Given the current evidence available regarding morbidity for SLN Bx versus END, the phase II will determine if patient-reported neck and shoulder function and related QOL at 6 months after surgery using the Neck Dissection Impairment Index (NDII) shows a signal of superiority of SLN Bx compared to END. A total of 228 randomized patients with negative PET/CT for potential evaluation of shoulder-related morbidity with difference in 6-month NDII scores (minimum important difference ³7.5; one-sided a = 0.10; 90% power) will serve as the “Go/No-Go” decision to move forward into phase III. The phase III portion is a non-inferiority (NI) trial with disease-free survival (DFS) as the primary endpoint (NI margin hazard ratio 1.34 based on a 5% absolute difference in 2-year DFS; one-sided alpha 0.05; 80% power, and an interim look for efficacy at 67% of the events based on an O’Brien-Fleming boundary). The NDII at 6 months after surgery is a hierarchical co-primary endpoint for the phase III. Target accrual of phase III is 618 PET/CT negative patients, including those randomized in phase II (297 DFS events required for the final analysis). In addition to radiotherapy and imaging credentialing, quality assurance will include central pathology review of all negative SLN Bx cases and surgeon credentialing through an education course and SLN Bx and END case review by the surgical co-chairs. A surgical quality assurance working group will review all trial SLN Bx and END outcomes. As of 02/15/21, 7 patients have been screened and 6 of the planned 228 randomized patients in phase II have been enrolled. Clinical trial information: NCT04333537.

4506 Background: Sorafenib is still the standard first-line therapy for advanced hepatocellular carcinoma (HCC). Donafenib, a novel multikinase inhibitor, showed potential benefits in a previous phase Ib study in HCC. Methods: In this open-label, randomized phase II/III trial (ZGDH3), patients with unresectable or metastatic HCC, a Child-Pugh liver function score ≤ 7, and no prior systemic therapy were enrolled from 37 sites across China and randomized (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). Efficacy analysis was primarily based on the full analysis set (FAS). Results: Between March 2016 and April 2018, 668 patients were randomized (donafenib, 334; sorafenib, 334) and included in the intention-to-treat (ITT) set, of whom 659 were analysed by FAS (328 vs 331). Donafenib was associated with a significantly longer median OS than sorafenib in both FAS (12.1 months vs 10.3 months, hazard ratio 0.831, 95% confidence interval 0.699–0.988, p = 0.0363) and ITT (12.0 months vs 10.1 months, 0.839, 0.706–0.996, p = 0.0446). There were no significant differences in median progression-free survival (3.7 months vs 3.6 months, p = 0.2824), objective response rate (4.6% vs 2.7%, p = 0.2448), and disease control rate (30.8% vs 28.7%, p = 0.5532). Grade 3 or worse adverse events (AEs) occurred in 191 (57.4%) and 224 (67.5%) patients ( p = 0.0082), respectively, and AEs of special interest and those leading to treatment interruption occurred in 287 (86.2%) vs 309 (93.1%, p = 0.0049) and 101 (30.3%) vs 141 (42.5%, p = 0.0013). A numerically lower number of patients reported serious AEs (55 [16.5%] vs 67 [20.2%], p = 0.2307) with donafenib. Common AEs with donafenib included hand-foot skin reaction (50.5%), aspartate aminotransferase increased (40.5%), blood bilirubin increased (39.0%), platelet count decreased (37.8%), and diarrhea (36.6%). Conclusions: Donafenib significantly improves OS over sorafenib with favourable safety and tolerability. Donafenib is a promising superior first-line therapy for advanced HCC. Funding: Zelgen. Clinical trial information: NCT02645981 .

4005 Background: The role of adjuvant chemotherapy after hepatectomy is controversial for liver only metastases from colorectal cancer (LM). Current recommendations for oxaliplatin-containing adjuvant regimen (FOLFOX) for LM are based on extrapolation of the results of the EORTC intergroup trial 40983, which showed that perioperative FOLFOX confirmed a progression-free survival benefit but did not affect overall survival (OS) in LM patients. We conducted a randomized controlled trial to determine if adjuvant modified FOLFOX (mFOLFOX) is superior to hepatectomy alone for LM. Methods: Eligible patients aged 20-75 years who had histologically proven colorectal adenocarcinoma with an unlimited number of LM were randomly assigned (1:1) to receive either adjuvant mFOLFOX6 (oxaliplatin 85mg/m2, l-LV 200 mg/m2, 5-FU bolus 400 mg/m2 and 2400mg/m2 over 48 h), for 12 cycles after surgery (CTX arm), or surgery alone (S alone arm). When treatment compliance after 9 courses of CTX was as high as expected in phase II, the registration was continued in phase III. The primary endpoint of phase III was disease-free survival (DFS), and the secondary endpoints were OS, toxicity, and sites of relapse. The planned sample size was 150 patients (pts) per arm, with a one-sided alpha of 5%, and 80% power detecting a 5y-DFS difference of 12% (25% with S alone vs. 37% with CTX). Results: Between Mar. 2007 and Jan. 2019, 300 patients were randomized. 151 pts were allocated to CTX, and 149 pts to S alone. When the third interim analysis of phase III was performed in Dec. 2019, the DSMC recommended the early termination of the trial because a statistically significant difference in terms of DFS but the futility in terms of OS was found. With a median follow-up period of 54 months for disease-free surviving patients, the 3y-DFS was 52.1% (95% CI 43.2 – 60.2) with CTX and 41.5% (33.2 – 49.6) with S alone (hazard ratio 0.63 [0.45 – 0.89], one-sided p = 0.002 < 0.0163 for the one-sided alpha level at the interim analysis). However, the 3y-OS was 86.6% (79.2-91.4) with CTX and 92.2% (86.0 – 95.8) with S alone (hazard ratio 1.35 [0.84 – 2.19]). The 5y-OS was 69.5% (59.6-77.5) with CTX and 83.0% (74.5-88.9) with S alone. Median OS after recurrence was 38.4 months in the CTX arm and 87.6 in the S alone arm. Conclusions: DFS did not correlate with OS for LM. Postoperative chemotherapy with mFOLFOX6 improves DFS but worsens OS over surgery alone due to more deaths after recurrence in the CTX arm. Adjuvant mFOLFOX is not beneficial to patients after hepatectomy for LM. Clinical trial information: UMIN000000653 .

4021 Background: The role of neoadjuvant chemotherapy, particularly for those with initially resectable CLM, is controversial. And the optimal regimen and duration to be used in the neoadjuvant setting is not established. We conducted prospective, multicenter, randomized phase II/III study to assess pre-operative 8 cycles of CAPOX-Bev (arm A) plus radical surgery compared with post-operative 8 cycles of CAPOX-Bev (arm B) for patients (pts) with resectable CLM. Methods: The primary endpoint in the Phase II was completion rate of protocol treatment (more than 6 cycles of CAPOX-Bev plus R0 surgical resection) and PFS in the Phase III. The secondary endpoints were OS, ORR (arm A), liver damage (arm A), safety. The Phase III part was terminated due to slow enrollment. Results: 81 pts were enrolled from 10 centers between November 2010 and November 2017. The full analysis set consisted of 76 pts who started protocol treatment (arm A 37 vs. arm B 39). 76 pts had the following characteristics: median age 66 (27-80), median number of liver metastases 2 (1-14), 69.7% male, 67.1% synchronous and 94.7% primary resected. Completion rate of protocol treatment was 89.2% in arm A and 71.8% in arm B (p = .06). ORR was 63.9%, including 2 pts who had pathologically complete response (5.6%). Only 1 pts in arm A could not undergo surgery due to progression of disease. In the chemotherapy safety population, arm B was associated with more grade 3 neutropenia and grade 3 gastrointestinal disorder than arm A. The most frequent surgical adverse event was biliary fistula, with an incidence of 0% in arm A and 10.3% in arm B (p = .02). No patient died from treatment-related adverse events. The median follow-up time was 40 months. The rate of PFS at 3 years was 32.2% in arm A versus 38.5% in arm B (p = .99). Conclusions: Pre-operative 8 cycles of CAPOX-Bev is compatible with radical surgery, but may have no impact on progression-free survival compared with post-operative chemotherapy. Clinical trial information: UMIN000003783 .

6502 Background: The standard treatment for post-operative high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (CDDP) (100 mg/m2, q3wk, 66 Gy/33Fr; 3-weekly CDDP+RT). However, one concern with 3-weekly CDDP+RT is insufficient CDDP compliance due to high-dose-related toxicities. Weekly CDDP+RT (40 mg/m2, qwk, 66 Gy/33Fr; weekly CDDP+RT) is an alternative regimen with better compliance. Here, we conducted a phase II/III trial of weekly CDDP+RT in post-operative high-risk LA-SCCHN. Methods: This is a multi-institutional randomized phase II/III trial to confirm the non-inferiority of weekly CDDP+RT (Arm B) compared with 3-weekly CDDP+RT (Arm A). The trial enrolled pts aged 20-75 years with post-operative high-risk features (microscopically positive margin and/or extranodal extension) and ECOG-PS 0-1. Pts were randomized in a 1:1 ratio to Arm A or Arm B. Primary endpoint of phase II was the proportion of treatment completion and that of phase III was overall survival (OS). A non-inferiority margin of hazard ratio (HR) was set at 1.32. Results: Between Oct 2012 and Dec 2018, 261 pts were enrolled (Arm A 132 pts, Arm B 129 pts). At the planned second interim analysis in phase III with 76/161 events, the Data and Safety Monitoring Committee recommended terminating the trial and publishing the results because the statistical boundary for OS non-inferiority had met the pre-specified stop criteria. With a median follow-up of 2.2 years in all randomized pts, 3-year OS was 59.1% in Arm A and 71.6% in Arm B with a HR of 0.69 (99.1% CI, 0.374-1.273 [ < 1.32], one-sided p for non-inferiority = 0.00272 < 0.00433). 3-year RFS was 53.0% in Arm A and 64.5% in Arm B with a HR of 0.71 (95% CI, 0.48-1.06). Regarding acute adverse events, neutropenia (≥ grade 3), increased creatinine (≥ grade 2), hearing impairment (≥ grade 2) and mucositis (≥ grade 2) occurred in 48.8%, 8.5%, 7.8% and 55.0% in Arm A and 35.3%, 5.7%, 2.5% and 59.0% in Arm B, respectively. For compliance, median total dose of CDDP was 280 mg/m2 (IQR, 250-299) in Arm A and 239 mg/m2 (IQR, 199-277) in Arm B. Total radiation dose was 66 Gy (IQR, 66-66) in both arms. Proportion of treatment completion was 93.2% in Arm A and 86.8% in Arm B. Conclusions: Weekly CDDP+RT is non-inferior to 3-weekly CDDP+RT for post-operative high-risk LA-SCCHN pts and has a favorable toxicity profile. Weekly CDDP+RT should be considered the new standard treatment option for these pts. Clinical trial information: 000009125 .

4126 Background: Despite recent progress of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), its survival remains limited. We conducted a randomized controlled trial to compare neoadjuvant chemotherapy (NAC) with upfront surgery (UP-S) for patients with resectable PDAC. Methods: Patients with resectable PDAC, all confirmed cytologically or histologically were enrolled. Patients received 2 cycles of gemcitabine and S-1 regimen (GS) followed by surgery (NAC) or UP-S after randomization (1:1). Patients in both arms received adjuvant chemotherapy using S-1 for 6 months after surgical resection. The primary endpoint was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. Results: A total 362 patients were randomly assigned to NAC-GS (n=182) or UP-S (n=180) for 3 years (2013-16). The median OS was 36.7 months in NAC-GS and 26.6 months in UP-S; HR 0.72 (p=0.015, stratified log-rank test) at 2.5 year after final enrollment. Crude resection rate for NAC and UP-S were 77%, 72% respectively. There was no operative mortality in both groups. Although G3/4 adverse events were observed frequently (73%) during NAC, no significant difference for both groups was observed for perioperative outcomes including blood loss, operation time, R0 resection rate and post-operative morbidity. Significant decrease of pathological nodal metastases in NAC was noted compared to those in UP-S by pathological evaluation for resected patients(p

TPS8578 Background: Multiple clinical trials have shown that prophylactic cranial irradiation (PCI) prevents brain metastases and may prolong survival in small cell lung cancer (SCLC). However,prophylactic cranial irradiation can lead to decline in cognitive function. Preclinical evidence suggests that the pathogenesis of this toxicity includes inflammatory injury to proliferating neuronal progenitor cells in the peri-hippocampal stem cell niches. We hypothesized that conformal avoidance of the hippocampal neural stem cell compartment during brain irradiation using intensity-modulated radiotherapy (IMRT) would decrease the likelihood and/or severity of this toxicity. This hypothesis was recently validated by positive results from NRG Oncology CC001, a phase III trial of hippocampal avoidance during whole-brain radiotherapy for patients with brain metastases. NRG Oncology CC003 is an ongoing randomized phase II/III trial of hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) for small cell lung cancer, conducted in parallel with NRG Oncology CC001. Methods: The primary endpoints of the phase IIR and III components are 12-month intracranial relapse rate and 6-month deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall, respectively. This is a seamless phase IIR/III trial, with the phase IIR designed to demonstrate non-inferiority. If the non-inferiority margin of the phase IIR component is not exceeded, then the trial would transition to the phase III component. Following accrual of 182 of planned 172 patients on the phase IIR component, the trial closed to accrual on 10/13/17 to assess the phase IIR primary endpoint. The DSMB evaluated the IIR outcomes, and on 1/9/19, the trial was reactivated to accrue an additional 122 patients to the phase III component. Eligibility criteria include: 1) small cell lung cancer with at least partial response to chemotherapy; 2) contrast-enhanced thin-slice volumetric MRI scan; and, 3) Zubrod performance status 0-2. Supported by grant UG1CA189867 (NCORP) from the National Cancer Institute. Clinical trial information: NCT02635009.

The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach. Clin Cancer Res; 19(10); 2646–56. ©2013 AACR.

TPS6097Background: Incidence of Oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing as a result of Human Papillomavirus (HPV), genotype 16 infection. Existing treatments for HPV+ OP...

TPS5603Background: Patients with metastatic or recurrent CC who are not amenable to curative treatment with surgery or radiation have a poor prognosis, and systemic chemotherapy is regarded as a st...

Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxelin vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered withEudraCT 2008-005221-11.

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label, adaptive design, phase II/III study of MOR208 + BEN vs RTX + BEN in adult patients with histologically confirmed DLBCL who have relapsed after or are refractory to 1 to 3 prior lines of therapy and who are not candidates for high-dose chemotherapy and autologous SCT. At least 1 prior therapy line must have included a CD20-targeted therapy. Other key inclusion criteria: age ≥18 years; measurable disease; availability of tumor tissue for central pathology review; ECOG 0–2, and adequate major organ systems function. Key exclusion criteria: primary refractory DLBCL; central nervous system involvement, and known double/triple hit DLBCL genetics. The safety of the combination will be assessed in an initial phase II evaluation. Treatment will comprise 6 cycles of MOR208 (12 mg/kg IV) + BEN (90 mg/m2 IV) or RTX 375 mg/m2 IV + BEN. Patients achieving a response after cycle 6 will continue to receive antibody treatment for up to 18 additional cycles. Primary endpoint: progression-free survival (PFS); secondary endpoints include: best overall response, overall survival, safety, quality of life, immunogenicity and pharmacokinetics. Enrollment of 330 patients is anticipated in Europe, US and Asia-Pacific countries. Fourteen patients have been randomized to date. Clinical trial information: NCT02763319.

Background and purpose To assess the efficacy and safety of olesoxime, a molecule with neuroprotective properties, in patients with amyotrophic lateral sclerosis (ALS) treated with riluzole. Methods A double-blind, randomized, placebo-controlled, multicenter trial of 18 months’ duration was conducted in 512 subjects, with probable or definite ALS and a slow vital capacity (SVC) ≥70%, receiving 330 mg olesoxime daily or matching placebo and 50 mg riluzole twice a day in all. The primary intention-to-treat (ITT) outcome analysis was 18 months’ survival. Secondary outcomes were rates of deterioration of the revised ALS functional rating scale (ALSFRS-R), focusing on the 9-month assessment, SVC and manual muscle testing. Blood levels, safety and tolerability of olesoxime were also assessed. Results At 18 months, 154 of the 512 ITT patients had died (79 of 253 placebo, 75 of 259 olesoxime). Estimated overall survival according to Kaplan–Meier analysis was 67.5% (95% CI 61.0%–73.1%) in the placebo group and 69.4% (95% CI 63.0%–74.9%) in the olesoxime group; hence survival was not significantly different between treatment arms (P = 0.71, stratified bulbar/spinal log-rank). The other efficacy end-points evaluated were also negative, with the exception of a small difference in ALSFRS-R global score at 9 months in favor of olesoxime but not sustained after 18 months’ treatment nor evident in either the stratified bulbar or spinal subpopulations. Treatment did not raise any safety concerns. Conclusions Olesoxime, although well tolerated, did not show a significant beneficial effect in ALS patients treated with riluzole.

189Background: Despite improvements of postoperative adjuvant therapy for resected pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor. A randomized controlled trial has begun to co...

TPS1146 Background: TNBC, which is characterized by a lack of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) overexpression, is associated ...

Bone morphogenetic proteins (BMPs) are important mediators of fracture repair. They include a group of bioactive proteins that are synthesized locally at a fracture site and work mostly by upregulating stem-cell differentiation, thereby stimulating bone formation. As such, BMPs are of major interest to orthopaedic surgeons as osteoinductive agents in patients with a difficult fracture in whom bone-healing is potentially compromised. Several BMPs, including recombinant human BMP-2 (rhBMP-2), have been characterized and synthesized via recombinant technology: bone formation is induced in a more or less dose-dependent fashion and may be given in quantities that vastly exceed physiologic amounts. rhBMP-2 has U.S. Food and Drug Administration approval for use in anterior lumbar spine fusions (2002) and for open tibial fractures (2004)1-3. A small number of studies have shown efficacy for …

TPS6099 Background: Clinical trial results from phase II trials to select an experimental treatment arm for separate phase III trial comparison can require years. Cancer clinical trials also now aim at both survival and PRO/functional outcomes, especially in head and neck (HN) studies. We developed a unique seamless phase II/III trial design to save on sample size and trial duration. The initial multi-arm phase II trial selects the most effective regimen among multiple experimental arms by first comparing each of the new treatments to a common control arm, using chosen endpoints, such as progression free survival. The winner will be tested for overall survival in the phase III study. Methods: We propose a phase II/III design to test the efficacy of experimental arms of postoperative radiation (RT) + docetaxel or RT + docetaxel + cetuximab in patients with HN squamous cancer. These are compared to the control arm of RT + cisplatin in the phase II part. Only one arm will be selected to go on to phase III depending on efficacy (PFS), PRO and safety outcomes. One experimental arm must be sufficiently better than the common control arm and the winner not having increased toxicity or functional cost to be selected for phase III inclusion. If not, the trial is halted for futility. Patients in the phase II selected arm and the control arm are included in phase III testing. Group sequential method is used to design each component. Separate interim efficacy and futility analyses are built in such that each endpoint can be monitored as in separate phase II, III trials. Once sample sizes are derived, operating characteristics for the seamless II/III design are evaluated through simulations under the null and various alternative hypotheses. Savings on sample size and time are compared to typical separate phase II and III designs and to the design testing only the arm of RT + docetaxel + cetuximab in phase II. Conclusion: The phase II/III RTOG 1216 HNC trial offers cost effectiveness, operational efficiency and scientific innovation.

e14645 Background: Chemoradiotherapy is the standard treatment option for patients with esophageal cancer unsuitable for surgery, but the majority of patients will die of their disease, most commonly with local tumor progression/recurrence. We initiated this study to determine the efficacy and safety of the addition of cetuximab with paclitaxel, cisplatin, and radiation for patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: A total of 127 patients with clinical stage II–IVa disease were selected to receive combined-modality therapy consisting of cetuximab (400 mg/m2/wk week 1, then 250 mg/m2/wk week 2-8), paclitaxel (45 mg/m2/wk) and cisplatin (20 mg/m2/wk) in weeks 2-8 with 59.4 Gy of radiation (Group A, n = 29) versus the same chemoradiotherapy schedule but without cetuximab (Group B, n = 98). Results: At the time of this analysis, 27 and 88 patients were available for evaluation of response and survival in Group A and B respectively. In Group A, 20 patients (74.1%) achieved complete response (CR) and 7 (25.9%) achieved partial response (PR), resulting in an objective response rate (ORR) of 100%. The 1- and 2-year progression-free survival (PFS) was 91.2% and 85.1%, the median PFS was not reached. No association between tumor EGFR expression and response or survival was found. In Group B, 33 patients (37.5%) achieved CR, 51 (58.0%) achieved PR and 4 (4.5%) had stable disease, thus the ORR was 95.5%. The 1- and 2-year PFS was 89.0% and 50.5%, with the median PFS of 24.3 months. The difference in PFS between the two groups was statistically significant (p = 0.011). Treatment-related toxicities were generally grade 1 or 2. The most common toxicities were rash (89.3%), followed by neutropenia (71.4%) and esophagitis (60.7%) in chemoradiation-plus-cetuximab group. Adverse events were most often neutropenia (81.8%) and esophagitis (76.1%) in chemoradiation group. Locoregional failure rate was 3.7% and 15.9% in Group A and B, respectively. Conclusions: Cetuximab can be safely administered with chemoradiation and may prolong progression-free survival for Chinese patients with ESCC.

5502 Background: CA4P, a vascular disrupting agent (VDA), has shown clinical activity as monotherapy in patients with ATC. Results include a durable CR in a phase I trial and a median survival of 4.7 months with 34% of patients alive at 6 months and 23% of patients alive at 1-year in a Phase 2 trial. Interim results previously presented from this phase II/III study evaluating CA4P in combination with carboplatin (C) + paclitaxel (P) in patients with ATC suggested a survival benefit with the combination therapy. Final survival and safety data are now available. Methods: This is a multicenter, open-label, 2:1 randomized trial for patients with histologically confirmed ATC. 80 out of 180 planned patients were randomized to receive up to 6 cycles of C + P with CA4P (CA4P Arm) or without CA4P (Control Arm). The targeted sample size of 180 patients was not reached due to slow enrollment. After 6 cycles of therapy, patients on the CA4P Arm without progression could continue to receive CA4P until disease progress...

3036 Background: As a targeted immunotherapy, the trifunctional antibody catumaxomab specifically binds to epithelial cell-adhesion molecule (EpCAM) on tumor cells and attracts T-cells via CD3 and accessory cells via its FcγRI/III+ region. The clinical relevance of this mode of action was demonstrated by Parsons et al. (ASCO 2008) in a pivotal phase II/III trial. Catumaxomab treatment resulted in a clinically relevant prolongation of puncture-free survival (defined as time to next puncture or time to death, which ever occurred first) in patients with malignant ascites. One of the most common adverse events associated with catumaxomab is cytokine-release-related-symptoms (CRRSs), which might be of predictive value for efficacy. Methods: The safety profile of catumaxomab was identified in the pivotal study. CRRSs (pyrexia, nausea, and vomiting) were among the most common adverse events in the catumaxomab group. A correlation between CRRSs and puncture-free survival, the primary endpoint, was performed to investigate whether patients who had CRRSs benefited from catumaxomab treatment more than those who had no CRRSs. Results: Among 157 patients, CRRSs were limited to the duration of catumaxomab treatment, with a median onset of 1 day after catumaxomab administration and a median duration of 1–2 days. Most of these symptoms were mild to moderate and were manageable by standard symptomatic treatment. Only 6 of 101 patients with CRRSs who were treated with concomitant medication required systemic corticoid therapy. Puncture-free survival was longer (48 days) in patients with (81%) CRRSs during catumaxomab treatment than in patients without (19%) CRRSs (27 days), although the difference was not statistically significant (p=0.1546, log rank test). Conclusions: CRRSs are a common occurrence with catumaxomab, due to its mode of action, during the treatment of patients with malignant ascites. Since CRRSs appear to be correlated with efficacy, they may therefore be a predictive factor for catumaxomab efficacy. [Table: see text]

3012 Background: IGN101 is a cancer vaccine acting via the epithelial cell adhesion molecule (EpCAM) expressed on epithelial cancers. It consists of 0.5 mg alum-adsorbed murine Mab 17–1A that bears...

Most drug trials in prostate cancer (PCa) concentrate on patients withhormone refractory disease. Drugs which work later in the disease may work better still if used earlier. STAMPEDE is an academic, investigator-initiated randomised controlled trial to test six treatment approaches for patients with high-risk localised or metastatic PCa who are commencing long-termhormone therapy (HT).

This paper describes a simple two-stage design for randomized clinical trials with a binary outcome. An early stopping criterion applies to results in the experimental arm only and seeks to evaluate that arm with respect to some external standard of efficacy. Stopping rules are similar to those commonly used in phase II designs. This design has no adverse impact on the overall type I error rate, though one must increase sample size to accommodate a modest loss in power.

7027 Background: E4599 was a phase II/III trial, in which 878 patients with advanced NSCLC were randomized to carboplatin + paclitaxel (PC arm) or PC + bevacizumab (PCB arm). Survival and progression free survival (PFS) were superior on the PCB arm (Sandler, ASCO 2005). The rationale for markers used in this correlative study were based on elevated vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (ICAM) in NSCLC and changes in response to endothelial apoptosis. Methods: Prospective laboratory correlates included measurements of pretreatment plasma VEGF as well as pretreatment and week 7, bFGF, ICAM, and E-Selectin. 166 patients had pre- and 112 had post-treatment measurements. Measurements were made by ELISA. Low and high levels were defined as ≤ or > than the median. Results: There were significant associations between E-Selectin and ICAM (p = .003) and between bFGF and VEGF (p = .01). E-Selectin (p = .01) and bFGF (p = .004) showed significant decreases from baseline at week 7 in both arms (Wilcoxon signed-rank tests). Only baseline ICAM showed a significant association with response. Patients with low baseline ICAM in both arms had a higher response rate of 29% vs 13% in high ICAM group (p=0.03, Fisher’s exact test). Patients with low baseline ICAM levels had a significantly better overall survival (p=0.00005) compared to patients with high ICAM levels as well as a better 1-year survival (65% vs 25%). No other factor predicted survival. Tests for treatment by factor interactions, which test whether the effect of treatment (the addition or not of bevacizumab) is different within the low and high levels were significant only for baseline ICAM where treatment interaction is significant for PFS (p=.04). This suggests a benefit from bevacizumab (53% reduction in the PFS hazard rate) in the group with low baseline ICAM levels vs no benefit from bevacizumab for patients with high levels. Conclusions: Baseline ICAM levels are strongly prognostic for survival and response to chemo. This exploratory correlative study suggests that improvements in PFS from the addition of bevacizumab occur mainly in patients with low baseline ICAM levels. [Table: see text]

5578 Background: Induction chemotherapy plus CRT vs. CRT as front line treatment have not been compare in LAHNC in randomised study. Recently, Zorat et al reported benefit in survival in patients w...